Hybrid immunity expands the functional humoral footprint of both mRNA and vector-based SARS-CoV-2 vaccines

ABSTRACT

Despite the successes of current COVID-19 vaccines, waning immunity, the emergence of variants of concern, and breakthrough infections among vaccinees, have begun to highlight opportunities to improve vaccine platforms. Real-world vaccine efficacy studies have highlighted the reduced risk of breakthrough infection and disease among individuals infected and vaccinated, referred to as hybrid immunity. Thus, we sought to define whether hybrid immunity shapes the humoral immune response to SARS-CoV-2 following Pfizer/BNT162b2, Moderna mRNA1273, ChadOx1/AZ1222, and Ad26.COV2.S vaccination. Each vaccine exhibits a unique functional humoral profile in vaccination only or hybrid immunity. However, hybrid immunity shows a unique augmentation of S2-domain-specific functional immunity that was poorly induced for the vaccination only. These data highlight the importance of natural infection in breaking the immunodominance away from the evolutionarily unstable S1-domain and potentially affording enhanced cross-variant protection by targeting the more highly conserved S2 domain of SARS-CoV-2. Graphical Kaplonek et al shows that mRNA- and vector-based SARS-CoV-2 vaccines display distinct immune profiles in individual vaccinated only or infected and vaccinated. The infection prior vaccination helps improving the immunity and triggers response to the more conserve domain of SARS-CoV-2 which might enhance the effectiveness of vaccines against new variants.